GSK-J1

Alias: GSKJ1; GSKJ 1; GSKJ-1
Cat No.:V1420 Purity: ≥98%
GSKJ1 (GSK-J1; GSK-J 1; GSK-J-1) is a novel, highly selective and potent inhibitor of histone demethylase (H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A) with potential antineoplastic activity.
GSK-J1 Chemical Structure CAS No.: 1373422-53-7
Product category: Topoisomerase
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

GSKJ1 (GSK-J1; GSK-J 1; GSK-J-1) is a novel, highly selective and potent inhibitor of histone demethylase (H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A) with potential antineoplastic activity. It that has significant activity (IC50 60 nM for human JmjD3) in vitro and in cell assays using an ester prodrug derivative (GSK-J4: 1 µM < IC50 < 10 µM; e.g. 9 µM in primary human macrophages). The methyl groups from tri- and dimethylated lysine 4 of histone H3 are removed by the KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases. KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) may play a role as oncogenic drivers, according to mounting evidence from primary tumors and model systems. As an ester derivative (GSK-J5) in cells and a control for target effects in vitro, the pyridine regioisomer GSK-J2 exhibits significantly less on-target activity (IC50 > 100 µM for human JmjD3). Recent data against H3K4me3/2/1 demethylases indicates that GSK-J1 also exhibits some activity (IC50 950 nM for Jarid1b, IC50 1.76 uM for Jarid1c).

Biological Activity I Assay Protocols (From Reference)
Targets
JMJD3 ( IC50 = 60 nM )
ln Vitro

GSK-J1 blocks the functions of JMJD3 and UTX that are transiently transfected in HEK-293 cells. GSK-J1 also raises total nuclear H3K27me3 levels, which prevents human primary macrophages from producing TNF-α.[1]
GSK-J1 raises global levels of H3K27me3 and decreases Runx2 and Osterix expressions as well as ALP activity in MC3T3-E1 cells.[2]

ln Vivo
GSK-J1, a JMJD3 small molecule inhibitor, directly disrupted the transcription of genes linked to inflammation by modifying their promoters with histone modification H3K27me3.
Enzyme Assay
Purified JmjD3 (1 μM) and UTX (3 μM) are incubated with a 10 μM peptide [Biotin-KAPRKQLATKAARK(me3)SAPATGG]. in 50 mM HEPES pH 7.5, 150 mM KCl, 50μM (NH4)2SO4·FeSO4·H2O, 1 mM 2-oxoglutarate, and 2 mM ascorbate (JmjD3, 3 minutes at 25°C; UTX, 20 minutes at 25°C) had different inhibitor concentrations (0, 0.005, 0.01, 0.02, 0.05, 0.1 μM). To halt the reaction, add 10 mM EDTA. Utilizing a zip tip to desalt the reaction, the reaction is then spotted using an α-cyano-4-hydroxycinnamic acid MALDI matrix on a MALDI plate. Via the MALDI-TOF R system, samples are analyzed.
Animal Protocol
100 mg/kg/day; i.p.; for 10 days
Mice harboring subcutaneous SF8628 K27M xenografts
References

[1]. Nature . 2012 Aug 16;488(7411):404-8.

[2]. J Cell Biochem . 2015 Nov;116(11):2628-36.

[3]. J Biol Chem . 2022 Jun;298(6):102017.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C22H23N5O2
Molecular Weight
389.45
Exact Mass
389.19
Elemental Analysis
C, 67.85; H, 5.95; N, 17.98; O, 8.22
CAS #
1373422-53-7
Appearance
Solid powder
SMILES
C1CN(CCC2=CC=CC=C21)C3=NC(=NC(=C3)NCCC(=O)O)C4=CC=CC=N4
InChi Key
AVZCPICCWKMZDT-UHFFFAOYSA-N
InChi Code
InChI=1S/C22H23N5O2/c28-21(29)8-12-24-19-15-20(26-22(25-19)18-7-3-4-11-23-18)27-13-9-16-5-1-2-6-17(16)10-14-27/h1-7,11,15H,8-10,12-14H2,(H,28,29)(H,24,25,26)
Chemical Name
3-[[2-pyridin-2-yl-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)pyrimidin-4-yl]amino]propanoic acid
Synonyms
GSKJ1; GSKJ 1; GSKJ-1
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 50~77 mg/mL (128.4~197.7 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.5677 mL 12.8386 mL 25.6772 mL
5 mM 0.5135 mL 2.5677 mL 5.1354 mL
10 mM 0.2568 mL 1.2839 mL 2.5677 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
  • Structure of the inhibitor GSK-J1 bound in the catalytic pocket of human JMJD3. Nature . 2012 Aug 16;488(7411):404-8
  • GSK-J1 is selective for H3K27 demethylases of the KDM6 subfamily and specifically binds to endogenous JMJD3. Nature . 2012 Aug 16;488(7411):404-8.
  • GSK-J1 inhibits TNF-α production by human primary macrophages in an H3K27-dependent manner. Nature . 2012 Aug 16;488(7411):404-8.
  • J Biol Chem . 2022 Jun;298(6):102017.
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